The objective of Project 2 is to ascertain how chronic environmental stress in combination with unfavorable genotypes via 2 new mechanistic pathways (hypothalamic-pituitary-adrenocortical [HPA] axis and oxidative stress) affects BP reactivity to acute stress and development of preclinical cardiovascular disease (CVD). The Project will study a cohort of 300 African Americans and 307 European Americans (mean age will be 25.5 yrs) who have been evaluated 14 times over a 17-year period. The continued follow-up of this cohort will allow us to examine the cumulative effects of environmental stress, genotypes and their interaction on the time course of the development of preclinical measures of CVD over a period of 22 years. Subjects will have hemodynamic measures and indices of HPA axis and oxidative stress assessed prior to and immediately following three acute laboratory challenges, as well as in the naturalistic field setting. Subjects will also have measures of preclinical CVD evaluated. Two key genes in each of the HPA and oxidative stress pathways will be assessed by a gene-wide approach with all variants within a candidate gene considered jointly. In context of the recent evidence suggesting that activation of HPA axis and oxidative stress play an important role in obesity related EH, we hypothesize that obesity will exacerbate the activation of these two pathways which are elevated by chronic environmental stress. Specific aims of Project 2 are to test the hypotheses that individuals from chronically stressful environments and/or with unfavorable genotypes will exhibit greater increases over time in HPA axis and oxidative stress response to acute stressors and chronic stress (i.e., natural environment assessment) and measures of preclinical CVD. Possible moderating influences of obesity will also be examined. We will also test the hypotheses that individuals with higher levels (when originally measured) and/or greater increases over time in HPA and oxidative stress responses to acute stress will exhibit higher levels of BP reactivity and measures of preclinical CVD. The long term objective of Project 2 is to improve the understanding of the way stress contributes to the development of EH. Findings will contribute to development of behavioral pharmacogenetic therapies which will include lifestyle interventions and pharmaceutical therapies in which the role of stress is taken into account. These efforts will result in more efficacious and personalized primary and secondary prevention approaches of EH and its co-morbidities.